1-Acylmethylbenzimidazole-2-sulfonic acids and their cyclization by N-nucleophiles

Article abstract of DOI:10.1134/S1070428014050169

New preparation method was developed for derivatives of 1,4-dihydro-1,2,4-triazino[4,3-a]-, 2-aryl-1(9)H-, and 1-R-imidazo[1,2-a] benzimidazole underlain by newly synthesized 1-acylmethylbenzimidazole-2- sulfonic acids. The latter react with 2-aminoethanol affording along with the previously described compounds of the 1-(2-hydroxyethyl)imidazobenzimidazole series also compounds of formerly unknown polycyclic system, 2,3,11,12-tetrahydro-1,3-oxazolo[2,3-a]imidazo[1,2-a]benzimidazole.

Full text of DOI:10.1134/S1070428014050169

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 5, pp. 716–724. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © T.A. Kuz’menko, L.N. Divaeva, A.S. Morkovnik, V.A. Anisimova, G.S. Borodkin, V.V. Kuz’menko, 2014, published in Zhurnal
Organicheskoi Khimii, 2014, Vol. 50, No. 5, pp. 727–734.
1-Acylmethylbenzimidazole-2-sulfonic Acids
and Their Cyclization by N-Nucleophiles
T. A. Kuz’menko, L. N. Divaeva, A. S. Morkovnik, V. A. Anisimova,
G. S. Borodkin, and V. V. Kuz’menko†
Research Institute of Physical and Organic Chemistry at Southern Federal University,
pr. Stachki 194/2, Rostov-on-Don, 344090 Russia
e-mail: asmork2@ipoc.rsu.ru
Received October 4, 2013
Abstract—New preparation method was developed for derivatives of 1,4-dihydro-1,2,4-triazino[4,3-а]-, 2-
aryl-1(9)Н-, and 1-R-imidazo[1,2-а]benzimidazole underlain by newly synthesized 1-acylmethylben-
zimidazole-2-sulfonic acids. The latter react with 2-aminoethanol affording along with the previously described
compounds of the 1-(2-hydroxyethyl)imidazobenzimidazole series also compounds of formerly unknown
polycyclic system, 2,3,11,12-tetrahydro-1,3-oxazolo[2,3-а]imidazo[1,2-а]benzimidazole.
DOI: 10.1134/S1070428014050169
Compound Iа successfully underwent cyclization
with hydrazine hydrate giving 3-phenyltriazinobenz-
imidazole (IIIа) (Scheme 1).
One method of the synthesis of compounds of
imidazo[1,2-а]benzimidazole series whose derivatives
are recommended for application in medicine as drugs
[1] is based on the intramolecular cyclization of 1-
acylmethyl-2-chlorobenzimidazoles under the action of
ammonia or primary amines [2]. The same procedure
but using hydrazine and its derivatives provides
substituted 1,4-dihydro-1,2,4-triazino[4,3-а]benzimi-
dazoles [3]. Compared with 2-chlorobenzimidazole the
benzimidazole-2-sulfonic acids readily exchanging the
sulfo group with nucleophiles are easier available
[4, 5]. Their direct N-alkylation is an efficient way to
simple and functionalized 1-alkyl-substituted
derivatives [6].
The cyclization of 1-acylmethyl-2-chlorobenzimi-
dazoles with ammonia and low boiling primary amines
into the corresponding derivatives of imidazo[1,2-а]-
benzimidazole occurs at heating under pressure [2].
We found that N-unsubstituted compounds IV are
easier obtained from sulfonic acid I by melting with
ammonium acetate at 130–140°С.
Compounds Iа and Ib like their 2-chloro-sub-
stituted analogs cleanly reacted with aniline providing
1-phenyl-2-R-imidazobenzimidazoles Vа and Vb. In
the 1Н NMR spectra (DMSO-d6) of compounds IV that
according to [7] exist in 9Н-tautomeric form and of 1-
substituted derivatives V the most downfield signal is
unexpectedly the proton Н3 (8.0–8.1 ppm), in contrast
to the pronounced π-excess in the imidazobenz-
imidazole system and to the occurrence of the
electrophilic substitution commonly at the position 3.
This fact is obviously due to the formation of the
electrostatically stabilized complexes of compounds
IV and V with DMSO, since in CDCl3 the signal of the
H3 proton shifts to the region 7.0 ppm. According to
the data of quantum-chemical calculations on the
potential energy surface (PES) of each among model
In this study the synthesis of previously unknown
bielectrophilic 1-acylmethylbenzimidazole-2-sulfonic
acids I is described and their heterocyclization under
the action of N-nucleophiles is examined. In aqueous
alcohol in the presence of 2 equiv of KОН [6] the
benzimidazole-2-sulfonic acid practically does not
undergo alkylation with phenacyl bromide, apparently
because of the competing decomposition of the initial
bromoketone. 1-Acylmethyl derivatives Iа–Ig form in
70–80% yields in anhydrous DMF from the
preliminary prepared dipotassium salt of benz-
imidazole-2-sulfonic acid (II).
†
Deceased.
716

1-ACYLMETHYLBENZIMIDAZOLE-2-SULFONIC ACIDS
717
Scheme 1.
R
N
N
NH2NH2
N
XCH2COR
N
SO3H
N
N
N
K
SO3K
N
H
CH2COR
Ia-Ig
II
IIIa
NH2(CH2)2OH
AcONH4
R'NH2
9
6
10
N
11
8
N
N
R
+
VII
12
7
N
N
R
N
5
N
N
H
N
R
O 1
4
R'
3
2
VIIIa, VIIIb, VIIId-VIIIf
Va, Vb, VIa, VIIa-VIIg, IXa, IXb, IXd, IXe
IVa, IVe, IVf
R = Ph (а), 4-CH3C6H4 (b), 4-OMeC6H4 (c), 4-BrC6H4 (d), 4-ClC6H4 (e), 4-FC6H4 (f), CH3 (g); R' = Ph (V), CH2CH2-N(CH2)5
(VI), (CH2)2OH (VII), (CH2)3OH (IX).
systems 1H- and 9H-imidazo[1,2-а]benzimidazole–
DMSO a couple of minima exists with close values of
energy with the maximum stabilization energies ΔEstab
–7.0 and –6.6 kcal mol−1 respectively,* where just the
proton H3 suffers the strongest deshielding effect from
the oxygen atom of DMSO. The calculation by GIAO
method [8] also confirms that the complex formation
with DMSO should result in the increase in the
chemical shift of the Н3 proton in both tautomers by
1.0–1.5 ppm. It concerns the atom H5 to a lesser extent,
and the signals of the other protons remain practically
unchanged (see the table).
VIа to obtain in high yield in one stage 1-dialkyl-
aminoalkyl derivatives of imidazo[1,2-а]benzimida-
zole possessing a versatile pharmacologic action [9, 10].
Sulfonic acids Iа, Ib and Id–If enter peculiarly in
reaction with 2-aminoethanol. In these reactions with
an overall yield of 85–90% along with the expected
derivatives of (2-hydroxyethyl)imidazobenzimidazole
VII formed previously unknown tetracyclic com-
pounds VIII. The products ratio essentially depends on
the electronic nature of the acyl substituent. 1-
Phenacyl-substituted sulfonic acid Ia underwent cycli-
zation giving an oxazolidine ring (yield of compound
VIIIа 38%), and its bromo- and chloroderivatives
converted into heterocycles VIIId and VIIIe in 49 and
61% yields respectively. Sulfonic acids Ic and Ig
A special preparative importance have the reactions
of acids I with dialkylaminoalkylamines which provide
a possibility as shown by an example of compound
Calculated chemical shifts (δ, ppm) of protons in 1H- and 9H-tautomers of imidazo[1,2-a]benzimidazole and their complexes
(1 : 1) with DMSO differing by stabilization energy ΔEstab
Complexes of 1Н-tautomer
Complexes of 9Н-tautomer
Proton no. 1H-tautomer
9H-tautomer
ΔEstab
ΔEstab
ΔEstab
ΔEstab
–7.0 kcal mol−1
–6.5 kcal mol−1
–6.6 kcal mol−1
–6.4 kcal mol−1
1
2
3
5
6
7
8
9
6.54
6.62
7.26
7.52
7.13
7.36
7.66
–
6.35
6.55
8.90
8.20
7.09
7.29
7.59
–
6.32
6.49
8.70
8.10
7.07
7.28
7.59
–
–
–
–
7.15
7.32
7.51
7.20
7.27
7.10
6.59
7.11
8.64
8.53
7.18
7.20
7.03
6.50
7.06
8.26
8.82
7.21
7.23
7.04
6.49
*
Calculated by the density functional method B3LYP/6-31G**.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 5 2014

KUZ’MENKO et al.
718
Scheme 2.
N
N
N
N
N
SO3H
NHCH2CH2OH
NCH2CH2OH
NCH2CH2OH
N
C+
R
R
OH
R
HO
C
A
HO(CH2)2NH2
I
VIII
_H+
N
N
N
HO(CH2)2NH2
SO3H
NH
SO3H
SO3H
R
N
N
N
NHCH2CH2OH
C+
C+
NHCH2CH2O _
C
O
R
R
B
formed only alcohol VIIc and VIIg in good yields. In
the 1H NMR spectrum of 2-methylimidazobenz-
imidazole VIIg the observed spin-spin coupling
between the protons H3 and 2-CH3 (3J 1.2 Hz) was
uncommonly strong for methylarenes(hetarenes).
Taking into account that the authentic 1-acyl-
methyl-2-(2-hydroxyethylamino)benzimidazoles at
heating in 2-aminoethanol are converted exclusively
into alcohols VII [11, 12], it is presumable that the
reaction of bielectrophilic sulfonic acids I with this
reagent starts by an attack on a carbonyl and not on the
sulfo group giving hemiaminals A and carbocations B.
Then follows a cascade cyclization along a single or
simultaneously along two routes distinguished by the
sequence of stages. In one variant first an oxazolidine
ring is closed in cations B, and afterwards the intra-
molecular substitution of the sulfo group provides the
imidazoline ring. In the alternative route in hemiaminal
А the sulfo group is attacked by the aminoethanol
residue, and first the imidazoline ring closes, and
thereafter through the heterocyclic carbocation C the
oxazolidine fragment is built up (Scheme 2).
The structure of tetracyclic scaffolds VIII was
1
1
confirmed by H NMR and mass spectra. Their H
NMR spectra are characterized by four incompletely
resolved signals (d.d.d) of nonequivalent protons of the
CH2CH2 fragment of the oxazolidine ring in the region
3.3–4.2 ppm and by two doublets of the imidazoline
methylene group at 4.1–4.6 ppm. The experimental
chemical shifts are in a good agreement with the
calculated values (Fig. 1).
7.27 (7.12-7.20)
7.41 (7.12-7.20)
Quantum-chemical calculations show that the
weakly nucleophilic ОН groups of aminoethanol
moieties in carbocations B and C cannot by themselves
attack the insufficiently electrophilic carbocation
centers (cf. [13]). The products of such attack with
oxonium oxygen atom have not even minima on PES.
However the cyclization becomes virtually a barrier-
less process if the OH group is preliminary ionized by
excess aminoethanol.
7.26 (7.12-7.20)
7.77 (7.58)
3.89 (4.14)
H11b
1.448
1.561
1.369
1.369
4.35 (4.57)
11a
H
1.469
1.479
4.24 (4.17)
H3b
1.431
7.63
H3a
The absence of oxazolidine derivatives at the
cyclization of sulfonic acids Ic and Ig is due either to
the difficulty of the formation of insufficiently
stabilized carbocations B and C (at R = Me), or by their
relatively low electrophilicity (at R = p-MeOC6H4).
3.08 (3.39)
(~7.42)
1.557
H2b
1.435
7.78 (~7.66)
H2a
7.57 (~7.42)
4.14 (4.0)
3.79 (3.86)
Fig. 1. The structure of the molecule of 12-phenyl-
2,3,11,12-tetrahydro-1,3-oxazolo[2,3-а]imidazo[1,2-а]ben-
zimidazole (VIIIа) (B3LYP/6-31**), bond lengths (Å),
calculated and experimental (in parentheses) chemical
shifts of protons (ppm).
The molecules of compounds VIII have a virtually
flat imidazobenzimidazole scaffold with the
oxazolidine ring located nearly orthogonally (Fig. 1).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 5 2014

1-ACYLMETHYLBENZIMIDAZOLE-2-SULFONIC ACIDS
719
1.714
1.623
96.4
98.1
1.873
1.869
143.0
TS1
Meisenheimer complex
1.242
1.520
96.2
1.267
147.9
101.0
1.921
97.4
1.547
TS2
Fig. 2. Transition states TS1, TS2 and Meisenheimer complex in the reaction of benzimidazole-2-sulfonic acid with ammonia.
The reaction of sulfonic acids I with 3-amino-
propan-1-ol is accompanied with strong tarring and
results in 2-aryl derivatives of 1-(3-hydroxypropyl)-
imidazobenzimidazole IX in an yield not exceeding
20%. We did not find tetracyclic structures like
compounds VIII with an oxazine ring that might form
as those obtained in [14].
characteristics nearly does not differ from TS1. Both
structures have the same symmetry Сs and the energy
difference less than 0.1 kcal mol−1.
The transformation of this complex in 2-amino-
benzimidazole occurs by two easily proceeding proton
transfers involving the ammonia (TS2, ΔE≠calc
~0.7 kcal mol−1, Fig. 2) and the proton of the NH
group of benzimidazole. Both protons move to the
oxygen atoms of the sulfo group; therewith the C–S
bond is totally destabilized, and the desulfuration com-
pletes by the elimination of the sulfurous acid molecule.
The course of N-substitution of the sulfo group in
the benzimidazole-2-sulfonic acid was not formerly
discussed. Quantum-chemical calculations performed
for a model system benzimidazole-2-sulfonic acid–
ammonia has shown that this multistage process starts
with the formation of a π-complex of ammonia
possessing a Сs-symmetry with a polar betaine form of
the sulfonic acid (μcalc 11.2 D) which is of enhanced
electrophilicity. The distance between the reacting
sites in the π-complex is 2.976 Å. Then through a less
polar tetrahedral transition state of relatively low
energy TS1 (μcalc 8.6 D) a transformation into
Meisenheimer complex occurs (ΔG≠calc 18.0, ΔH≠calc
5.4 kcal mol−1 with respect to reagents in the gas
phase) (Fig. 2). The latter in geometric and energy
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer
1
Specord 75IR. H NMR spectra were registered on a
spectrometer Varian Unity-300 (300 MHz). Chemical
shifts of protons are given with respect to the residual
protons of deuterated solvent. Mass spectrum of
electron impact (70 eV) was obtained on an instrument
Finnigan MAT INCOS 50 with the direct admission of
the sample into the ion source.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 5 2014

KUZ’MENKO et al.
720
The reaction progress was monitored and the
(DMF–Н2О, 9 : 1). IR spectrum, ν, cm–1: 3113–3456
(ОH), 1692 (С=О). Н NMR spectrum (DMSO-d6), δ,
1
homogeneity of compounds was checked by TLC on
plates with Al2O3 of III activity grade, eluent CHCl3,
development in iodine vapor in a humid chamber.
ppm: 2.43 s (3Н, Me), 6.35 s (2Н, СН2), 7.44 d (2Н,
Н3',5', J 8.1 Hz), 7.58–7.63 m (2Н, Н5,6), 7.75–7.85 m
(1Н, Н4 or 7), 7.95–8.045 m (3Н, Н7 or 4,2',6', J 7.1 Hz).
Found, %: С 58.26; Н 4.14; N 8.61; S 9.57.
С16Н14N2O4S. Calculated, %: С 58.17; Н 4.27; N 8.48;
S 9.71.
The optimization of geometry of molecules,
complexes, and transition states TS2 was carried out
using the program Firefly 8.0 [15], partially based on
the code of the program GAMESS [16]. The
calculation of the energy of the found structures was
performed with accounting for the correction for the
oscillation energy of the zero level applying the scaling
factor 0.961 [17]. The calculation of the chemical
shifts of protons of imidazo[1,2-a]benzimidazole and
its complexes with DMSO by GIAO method was
carried out using program GAUSSIAN 03 with
functional B3LYP, basis 6-31G** [18]. In event of
compound VIIIа the method SOS DFPT [19] was
applied in program version DeMon [20] (theory level
B3LYP/6-31G**//PW91-PW91/IGLOII).
1-[2-(4-Methoxyphenyl)-2-oxoethyl]benzimi-
dazole-2-sulfonic acid (Ic). Yield 80%, mp 328–330°С
(DMF). IR spectrum, ν, cm–1: 3354 (ОH), 1687 (С=О).
1Н NMR spectrum (DMSO-d6), δ, ppm: 3.88 s (3Н,
OMe), 6.33 s (2Н, СН2), 7.15 d (2Н, Н3',5', J 6.9 Hz),
7.58–7.64 m (2Н, Н5,6), 7.79–7.82 m (1Н, Н4 or 7),
7.90–7.97 m (1Н, Н7 or 4), 8.05 d (2Н, Н2',6', J 6.9 Hz).
Found, %: С 55.31; Н 4.18; N 8.19; S 9.13.
С16Н14N2O5S. Calculated, %: С 55.48; Н 4.07; N 8.09;
S 9.26.
1-[2-(4-Bromophenyl)-2-oxoethyl]benzimi-
dazole-2-sulfonic acidа (Id). Yield 88%, mp 264–
266°С (DMF–Н2О, 9 : 1). IR spectrum, ν, cm–1: 3398
Benzimidazole-2-sulfonic acid was synthesized by
procedure [21].
1
(ОH), 1696 (С=О). Н NMR spectrum (DMSO-d6), δ,
1-Acylmethylbenzimidazole-2-sulfonic acids Iа–
Ig. To a solution of 13.4 g (0.2 mol) of KОН
(recalculated to 85% concn.) in 40 mL of water was
added by portions 19.8 g (0.1 mol) of benzimidazole-
2-sulfonic acid maintaining the mixture temperature no
higher than 45–50°С. On cooling the dipotassium salt
of benzimidazole-2-sulfonic acid (II) was precipitated
by adding 100 mL of acetone, the precipitate was
filtered off, washed with acetone, dried at 50–60°С.
Yield 26 g (95%).
ppm: 6.35 s (2Н, СН2), 7.58–7.66 m (2Н, Н5,6), 7.72–
7.875 m (1Н, Н4 or 7), 7.85 d (2Н, Н3',5', J 8.6 Hz),
7.96–8.05 m (1Н, Н7 or 4), 8.20–8.46 m (2Н, Н2',6').
Found, %: С 45.43; Н 2.94; Br 20.11; N 7.14; S 8.11.
С15Н11BrN2O4S. Calculated, %: С 45.58; Н 2.81; Br
20.22; N 7.09; S 8.11.
1-[2-Oxo-2-(4-chlorophenyl)ethyl]benzimi-
dazole-2-sulfonic acid (Ie). Yield 85%, mp 282–283°С
(DMF–Н2О, 9 : 1). IR spectrum, ν, cm–1: 3455–3172
1
(ОH), 1684 (С=О). Н NMR spectrum (DMSO-d6), δ,
Slurry of 15 mmol of dipotassium salt II and
15 mmol of an appropriate haloketone in 10 mL of DMF
was stirred for 2 h at 80–85°С. On cooling the reaction
mixture was diluted with 20 mL of water, acidified
with conc. HCl till рН 1, the separated precipitate was
filtered off, washed with water and acetone.
ppm: 6.36 s (2Н, СН2), 7.58–7.66 m (2Н, Н5,6), 7.71 d
(2Н, Н3',5', J 8.6 Hz), 7.77–7.82 m (1Н, Н4 or 7), 7.97–
8.02 m (1Н, Н7 or 4), 8.09 d (2Н, Н2',6', J 8.7 Hz).
Found, %: С 51.49; Н 2.98; Cl 10.27; N 8.12; S 9.14.
С15Н11ClN2O4S. Calculated, %: С 51.36; Н 3.16; Cl
10.11; N 7.99; S 9.14.
1-(2-Oxo-2-phenylethyl)benzimidazole-2-sulfo-
nic acid (Iа). Yield 71%, mp 307–309°С (DMF–Н2О,
9 : 1). IR spectrum, ν, cm–1: 3477 (ОH), 1688 (С=О).
1Н NMR spectrum (DMSO-d6), δ, ppm: 6.12 s (2Н,
СН2), 7.20–7.24 m (2Н, Н5,6), 7.42–7.46 m (1Н, Н4 or 7),
7.57–7.71 m (4Н, Н7 or 4,3'–5'), 8.01–8.04 d (2Н, Н2',6', J
7.1 Hz). Found, %: С 57.10; Н 3.74; N 9.10; S 9.96.
С15Н12N2O4S. Calculated, %: С 56.95; Н 3.82; N 8.86;
S 10.14.
1-[2-Oxo-2-(4-fluorophenyl)ethyl]benzimidazole-
2-sulfonic acid (If). Yield 88%, mp 303–307°С
(DMF). 1Н NMR spectrum (DMSO-d6), δ, ppm: 6.35 s
(2Н, СН2), 7.31–7.37 m (2Н, Н5,6), 7.56–7.60 m (2Н,
Н3',5'), 7.80 d (1Н, Н4 or 7, J 7.7 Hz), 7.91 d (1Н, Н7 or 4
,
J 7.8 Hz), 8.16–8.21 m (2Н, Н2',6', J 8.6 Hz). Found,
%: N 8.12. С15Н11FN2O4S. Calculated, %: N 8.38.
1-(2-Oxopropyl)benzimidazole-2-sulfonic acid
1-[2-(4-Methylphenyl)-2-oxoethyl]benzimida-
zole-2-sulfonic acid (Ib). Yield 72%, mp 302–304°С
(Ig). Yield 81%, mp 316–317°С (Н2О). IR spectrum,
1
ν, cm–1: 3445–3186 (ОH), 1713 (С=О). Н NMR
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1-ACYLMETHYLBENZIMIDAZOLE-2-SULFONIC ACIDS
721
spectrum (DMSO-d6), δ, ppm: 2.28 s (3Н, Me), 5.67 s
(2Н, СН2), 7.58–7.66 m (2Н, Н5,6), 7.72–7.78 m (1Н,
Н4 or 7), 7.86–7.93 m (1Н, Н7 or 4). Found, %: С 47.08;
Н 4.12; N 10.94; S 12.71. С10Н10N2O4S. Calculated,
%: С 47.24; Н 3.96; N 11.02; S 12.61.
2-(4-Methylphenyl)-1-phenylimidazo[1,2-а]benz-
imidazole (Vb) was prepared similarly to compound
Va from sulfonic acid Ib. Yield 62%, mp 200–201°С
1
(EtOH). Н NMR spectrum (CDCl3), δ, ppm: 2.34 s
(3Н, Me), 7.13–7.18 m (5Н, Н3',5',3''–5''), 7.25–7.31 m
(2Н, Н3,6 or 7), 7.40–7.42 m (5Н, Н7 or 6,2',6',2'',6''), 7.61 d
3-Phenyl-1,4-dihydro-1,2,4-triazino[4,3-а]benz-
imidazole (IIIа). A solution of 0.32 g (1 mmol) of
sulfonic acid Ia in 3 mL of hydrazine hydrate was
bolied for 2h. The reaction mixture was cooled, the
separated precipitate was filtered off and washed with
water. Yield 0.21 g (86%), mp 305–306°С (DMF)
1
(1Н, Н5 or 8, J 8.1 Hz), 7.72 d (1Н, Н8 or 5, J 8.1 Hz). Н
NMR spectrum (DMSO-d6), δ, ppm: 2.34 s (3Н, СН3),
7.04–7.20 m (6Н, Н6 or 7,3',5',3''–5''), 7.33–7.47 m (6Н,
Н7 or 6,5 or 8,2',6',2'',6''), 7.73 d (1Н, Н8 or 5, J 8.1 Hz), 7.96 s
(1Н, Н3). Found, %: С 81.63; Н 5.37; N 13.10.
С22Н17N3. Calculated, %: С 81.71; Н 5.30; N 13.00.
1
(305–308°С [3]). Н NMR spectrum (DMSO-d6), δ,
ppm: 5.28 s (2Н, СН2), 7.06–7.15 m (2Н, Н7,8), 7.35–
7.51 m (5Н, Н6,9,3'–5'), 7.81–7.84 m (2Н, Н2',6'), 11.50 s
(1Н, NH).
1-[2-(Piperidin-1-yl)ethyl]-2-phenylimidazo-
[1,2-а]benzimidazole dihydrochloride (VIа). A mix-
ture of 0.95 g (3 mmol) of sulfonic acid Iа and
0.9 mL (6 mmol) of 2-(piperidin-1-yl)ethanamine was
heated at 140–150°С for 1 h. On cooling the reaction
mixture was treated with 15 mL of water, insoluble
oily residue was dissolved in chloroform and subjected
to chromatography on a column packed with Al2O3
(2 × 5 cm), eluent chloroform, collecting the fraction
with compound of Rf 0.3. The residue obtained by
evaporating chloroform was dissolved in acetone and
treated with HCl solution in ethyl ether till рН 1. Yield
0.9 g (72%), mp 223–224°С (223–224°С [23]).
2-Aryl-1(9)Н-imidazo[1,2-а]benzimidazoles IVа,
IVe and IVf. A melt of 1 mmol of sulfonic acid I in 3 g
of ammonium acetate was heated at 135–145°С for 1 h.
On cooling the melt was treated with 10 mL of water,
the precipitate was filtered off and washed with water
and acetone.
2-Phenyl-1(9)Н-imidazo[1,2-а]benzimidazole
(IVа). Yield 72%, mp 305–306°С (DMF) (285–287°С
[2], 310°С [22]).
Reaction of sulfonic acid I with 2-aminoethanol.
A mixture of 2 mmol of 1-acylmethylsulfonic acid I
and 8 mmol (0.5 mL) of 2-aminoethanol was heated at
150–160°С for 1 h, cooled, treated with 10–15 mL of
water, the precipitate was filtered off, dissolved in
chloroform, and chromatographed on a column packed
with Al2O3 (2 × 20 cm), eluent chloroform. First
compound VIII was isolated, Rf 0.8, then derivatives
of 2-(1Н-imidazo[1,2-а]benzimidazol-1-yl)ethanol
VII, Rf 0.2.) Compounds VIII did not form from acids
Ic and Ig.
2-(4-Chlorophenyl)-1(9)Н-imidazo[1,2-а]benz-
imidazole (IVe). Yield 75%, mp 316–317°С (DMF).
1Н NMR spectrum (DMSO-d6), δ, ppm: 7.15 t (1Н,
Н6 or 7, J 7.8 Hz), 7.25 t (1Н, Н7 or 6, J 7.8 Hz), 7.37–
7.44 m (3Н, Н5 or 8,3',5'), 7.70 d (1Н, Н8 or 5, J 7.8 Hz),
7.83 d (2Н, Н2',6', J 8.4 Hz), 8.17 s (1Н, Н3), 11.65 s
(1Н, NH). Found, %: С 67.34; Н 3.85; Сl 13.34; N
15.58. С15Н10ClN3. Calculated, %: С 67.30; Н 3.77; Сl
13.24; N 15.70.
2-(4-Fluorophenyl)-1(9)Н-imidazo[1,2-а]benz-
imidazole (IVf). Yield 75%, mp 325–327°С (DMF).
1Н NMR spectrum (DMSO-d6), δ, ppm: 7.13–7.27 m
(4Н, Н6,7,3',5'), 7.38 d (1Н, Н5 or 8, J 7.5 Hz), 7.70 d (1Н,
Н8 or 5, J 7.8 Hz), 7.82–7.87 m (2Н, Н2',6'), 8.13 s (1Н,
Н3), 11.70 s (1Н, NH). Found, %: N 16.62. С15Н10FN3.
Calculated, %: N 16.72.
2-(2-Phenyl-1Н-imidazo[1,2-a]benzimidazol-1-
yl)ethanol (VIIа). Yield 47%, mp 167–168°С (EtOH)
1
(166–168°С [2], 168–169°С [12]). Н NMR spectrum
(DMSO-d6), δ, ppm: 3.75–3.85 m (2Н, NСН2), 4.05–
4.10 m (2Н, OСН2), 5.11 br.s (1Н, ОН), 7.07 t (1Н,
Н6 or 7), 7.22 t (1Н, Н7 or 6), 7.48–7.56 m (4Н, Н5 or 8,3'–5'),
7.68 d (2Н, Н2',6'), 7.78 d (1Н, Н8 or 5), 7.89 s (1Н, Н3).
1,2-Diphenylimidazo[1,2-а]benzimidazole (Vа).
A solution of 0.63 g (2 mmol) of sulfonic acid Ia in 2 mL
of aniline was boiled for 2h, cooled, and diluted with 5 mL
of ethyl ether. The formed precipitate was filtered off.
Yield 0.4 g (54%), mp 209–210°С (EtOH) (204–206°С
[2]). 1Н NMR spectrum (DMSO-d6), δ, ppm: 7.13 t (1Н,
2-{2-(4-Methylphenyl)-1Н-imidazo[1,2-a]benz-
imidazol-1-yl}ethanol (VIIb). Yield 48%, mp 174–
1
175°С (С6Н6) (168–170°С [23]). Н NMR spectrum
(CDCl3), δ, ppm: 2.44 s (3Н, Me), 4.03–4.07 m (2Н,
NСН2), 4.21–4.26 m (2Н, OСН2), 4.85 br.s (1Н, ОН),
7.19 t (1Н, Н6 or 7, J 7.7 Hz), 7.30–7.38 m (6Н,
Н6 or 7), 7.23 t (1Н, Н7 or 6), 7.29–7.53 m (11Н, 10НPh
Н
+
5 or 8), 7.83 d (1Н, Н8 or 5, J 7.8 Hz), 8.21 s (1Н, Н3).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 5 2014

KUZ’MENKO et al.
3,7 or 6,2',3',5',6'), 7.59 d (1Н, Н5 or 8, J 8.0 Hz), 7.68 d (CDCl3), δ, ppm: 3.39 d.d.d (1Н, Н3A, 2J 10.0, 3J 8.2, 3J
722
Н
2
3
(1Н, Н8 or 5, J 8.1 Hz).
6.5 Hz), 3.86 d.d.d (1Н, Н2A, J 8.0, 3J 8.1, J 4.9 Hz),
2
3
3
4.00 d.d.d (1Н, H2B, J 7.8, J 7.8, J 6.5 Hz), 4.14 d
2-{2-(4-Methoxyphenyl)-1Н-imidazo[1,2-a]benz-
imidazol-1-yl}ethanol (VIIc). Yield 81%, mp 189–
(1Н, Н11B, J 10.9 Hz), 4.17 d.d.d (1Н, Н3B, J 10.1, J
7.8, 3J 4.9 Hz), 4.57 d (1Н, Н11A, J 11.0 Hz), 7.12–7.20
m (3Н, Н7–9), 7.38–7.46 m (3Н, Н3'–5'), 7.58 d (1Н, Н6,
J 7.3 Hz), 7.62–7.70 m (2Н, Н2',6'). Mass spectrum, m/z
(Irel, %): 277 (60.8) [M]+, 246 (8.3), 172 (8.3), 117
(10.0), 105 (98.0), 90 (10.0), 77 (54.6), 51 (16.6).
Found, %: С 73.49; Н 5.60; N 15.03. С17Н15N3О.
Calculated, %: С 73.63; Н 5.45; N 15.15.
2
3
1
190°С (EtOH) (188–190°С [2], 187–188°С [11]). Н
NMR spectrum (CDCl3), δ, ppm: 3.88 s (3Н, OMe),
4.09–4.12 m (4Н, СН2СН2), 5.95 br.s (1Н, ОН), 7.02 d
(2Н, Н3',5', J 8.8 Hz), 7.13 t (1Н, Н6 or 7, J 7.8 Hz), 7.17
с (1Н, Н3), 7.28 t (1Н, Н7 or 6, J 8.0 Hz), 7.40 d (2Н,
Н2',6', J 8.8 Hz), 7.55 d (1Н, Н5 or 8, J 7.8 Hz), 7.65 d
(1Н, Н8 or 5, J 8.1 Hz).
12-(4-Methylphenyl)-2,3,11,12-tetrahydro-1,3-
oxazolo[2,3-а]imidazo[1,2-а]benzimidazole (VIIIb).
Yield 38%, mp 176–178°С (benzene–octane, 2 : 1). IR
spectrum, ν, cm–1: 1629, 1590, 1547. 1Н NMR
spectrum (CDCl3), δ, ppm: 2.39 s (3Н, Me), 3.40 d.d.d
2-{2-(4-Bromophenyl)-1Н-imidazo[1,2-a]benz-
imidazol-1-yl}ethanol (VIId). Yield 28%, mp 197–
198°С (EtOH) (184–185°С [2], 197–198°С [12]). Н
NMR spectrum (CDCl3), δ, ppm: 4.07–4.15 m [4Н,
(СН2)2], 5.69 br.s (1Н, ОН), 7.15 t (1Н, Н6 or 7, J
7.7 Hz), 7.25 s (1Н, Н3), 7.80 t (1Н, Н7 or 6, J 7.7 Hz),
7.37 d (2Н, Н3',5'), 7.56 d (1Н, Н5 or 8, J 7.9 Hz), 7.64 d
(2Н, Н2',6', J 8.5 Hz), 7.66 d (1Н, Н8 or 5, J 7.6 Hz).
1
2
3
3
(1Н, Н3A, J 11.3, J 8.3, J 6.6 Hz), 3.85 d.d.d (1Н,
2
3
3
2
Н2A, J 8.1, J 8.1, J 5.0 Hz), 4.01 d.d.d (1Н, H2B, J
3
3
7.9, J 7.9, J 6.6 Hz), 4.15 d (1Н, Н11B, J 11.1 Hz),
4.18 d.d.d (1Н, Н3B, J 11.3, J 7.9, J 5.0 Hz), 4.57 d
(1Н, Н11A, J 11.0 Hz), 7.13–7.21 m (3Н, Н7–9), 7.24 d
(2Н, Н3',5' , J 7.8 Hz), 7.51 d (2Н, Н2',6', J 7.9 Hz), 7.60
d (1Н, Н6, J 7.9 Hz). Found, %: С 74.32; Н 6.03; N
14.31. С18Н17N3О. Calculated, %: С 74.21; Н 5.88; N
14.42.
2
3
3
2-{2-(4-Chlorophenyl)-1Н-imidazo[1,2-a]benz-
imidazol-1-yl}ethanol (VIIe). Yield 23%, mp 196–
197°С (EtOH) (194°С [9]). 1Н NMR spectrum
(CDCl3), δ, ppm: 4.05–4.08 m [4Н, (СН2)2], 5.87 br.s
(1Н, ОН), 7.14 t (1Н, Н6 or 7, J 8.0 Hz), 7.22 s (1Н, Н3),
7.29 t (1Н, Н7 or 6, J 7.4 Hz), 7.43 d (2Н, Н3',5', J 8.4 Hz),
7.49 d (2Н, Н2',6', J 8.7 Hz), 7.55 d (1Н, Н5 or 8, J 7.9 Hz),
7.65 d (1Н, Н8 or 5, J 8.0 Hz).
12-(4-Bromophenyl)-2,3,11,12-tetrahydro-1,3-
oxazolo[2,3-а]imidazo[1,2-а]benzimidazole (VIIId).
Yield 49%, mp 190–191°С (EtOH). IR spectrum, ν,
1
cm–1: 1628, 1590, 1553. Н NMR spectrum (CDCl3),
2-{2-(4-Fluorophenyl)-1Н-imidazo[1,2-a]benz-
imidazol-1-yl}ethanol (VIIf). Yield 39%, mp 194–
δ, ppm: 3.36 d.d.d (1Н, Н3A, 2J 11.1, 3J 8,2, 3J 6.8 Hz),
1
2
3
3
3.83 d.d.d (1Н, Н2A, J 8.1, J 8.0, J 4.8 Hz), 4.00
195°С (i-PrOH). Н NMR spectrum (CDCl3), δ, ppm:
d.d.d (1Н, H2B, J 7.9, J 7.8, J 6.8 Hz), 4.10 d (1Н,
2
3
3
4.06–4.11 m [4Н, (СН2)2], 6.00 br.s (1Н, ОН), 7.11 t
(1Н, Н6 or 7, J 7.6 Hz), 7.17 s (1Н, Н3), 7.18 t (2Н,
Н3',5', J 8.5, 8.5 Hz), 7.26 t (1H, Н7 or 6, J 7.9 Hz), 7.48
d.d (2Н, Н2',6', J 8.7, 5.3 Hz), 7.52 d (1Н, Н5 or 8, J 7.6 Hz),
7.61 d (1Н, Н8 or 5, J 8.2 Hz). Found, %: N 14.08.
С17Н14FN3О. Calculated, %: N 14.23.
Н
11B, J 10.9 Hz), 4.22 d.d.d (1Н, Н3B, 2J 11.1, 3J 8.2, 3J
4.8 Hz), 4.55 d (1Н, Н11A, J 11.0 Hz), 7.12–7.20 m
(3Н, Н7–9), 7.51 d (2Н, Н2',6', J 8.7 Hz), 7.55 d (1Н, Н6,
J 7.5 Hz), 7.56 d (2Н, Н3',5', J 8.8 Hz). Found, %: С
57.43; Н 4.11; Br 22.30; N 11.97. С17Н14BrN3О.
Calculated, %: С 57.32; Н 3.96; Br 22.43; N 11.80.
2-(2-Methyl-1Н-imidazo[1,2-a]benzimidazol-1-
yl}ethanol (VIIg). Yield 81%, mp 168–169°С
12-(4-Chlorophenyl)-2,3,11,12-tetrahydro-1,3-
oxazolo[2,3-а]imidazo[1,2-а]benzimidazole (VIIIe).
Yield 61%, mp 181–182°С (EtOH). IR spectrum, ν,
1
(toluene) (167–169°С [2], 162–163°С [12]). Н NMR
spectrum (CDCl3), δ, ppm: 2.33 d (3Н, Me, J 1.2 Hz),
4.10–4.15 m [4Н, (СН2)2], 5.85 br.s (1Н, ОН), 6.98 q
(1Н, Н3, J 1.3 Hz), 7.11 t (1Н, Н6 or 7, J 7.7 Hz), 7.26 t
(1Н, Н7 or 6, J 8.3 Hz), 7.48 d (1Н, Н5 or 8, J 8.0 Hz),
7.61 d (1Н, Н8 or 5, J 7.6 Hz).
1
cm–1: 1636, 1590, 1556. Н NMR spectrum (CDCl3),
δ, ppm: 3.37 d.d.d (1Н, Н3A, 2J 11.4, 3J 8.2, 3J 6.7 Hz),
2
3
3
3.84 d.d.d (1Н, Н2A, J 8.1, J 8.0, J 4.9 Hz), 4.02
d.d.d (1Н, H2B, J 7.8, J 7.8, J 6.7 Hz), 4.10 d (1Н,
Н11B, J 11.0 Hz), 4.23 d.d.d (1Н, Н3B, 2J 11.5, 3J 7.8, 3J
4.9 Hz), 4.56 d (1Н, Н11A, J 10.1 Hz), 7.12–7.20 m
(3Н, Н7–9), 7.41 d (2Н, Н2',6', J 8.6 Hz), 7.57 d (1Н, Н6,
J 6.7 Hz), 7.59 d (2Н, Н3',5', J 8.6 Hz). Found, %: С
2
3
3
12-Phenyl-2,3,11,12-tetrahydro-1,3-oxazolo-
[2,3-а]imidazo[1,2-а]benzimidazole (VIIIа). Yield
38%, mp 157–157°С (benzene–octane, 2 : 1). IR spec-
1
trum, ν, cm–1: 1630, 1590, 1546. Н NMR spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 5 2014

1-ACYLMETHYLBENZIMIDAZOLE-2-SULFONIC ACIDS
723
65.57; Н 4.42; Cl 11.25; N 13.60. С17Н14ClN3О.
Calculated, %: С 65.49; Н 4.53; Cl 11.37; N 13.48.
5.8 Hz), 3.58 t (2Н, NСН2, J 5.7 Hz), 4.20 t (2Н,
ОСН2, J 6.0 Hz), 5.73 br.s (1Н, ОН), 7.14 t (1Н, Н6 or 7
,
J 7.2 Hz), 7.24 s (1Н, Н3), 7.31 t (1Н, Н7 or 6, J
12-(4-Fluorophenyl)-2,3,11,12-tetrahydro-1,3-
oxazolo[2,3-а]imidazo[1,2-а]benzimidazole (VIIIf).
Yield 34%, mp 153–154°С (toluene). 1Н NMR
7.5 Hz), 7.40–7.48 m (4Н, Н2',3',5',6'),7.56 d (1Н, Н5 or 8
J 7.8 Hz), 7.65 с (1Н, Н8 or 5, J 8.1 Hz).
,
2
spectrum (CDCl3), δ, ppm: 3.34 d.d.d (1Н, Н3A, J
The study was carried out using the equipment of
the Center of joint use “Molecular Spectroscopy” of
the Research Institute of Physical and Organic
Chemistry at Southern Federal University.
3
3
2
3
11.5, J 8.3, J 6.7 Hz), 3.83 d.d.d (1Н, Н2A, J 8.1, J
8.0, J 4.9 Hz), 4.00 d.d.d (1Н, H2B, J 7.9, J 7.8, J
6.7 Hz), 4.07 d (1Н, Н11B, J 11.0 Hz), 4.11 d.d.d (1Н,
Н3B, 2J 11.5, 3J 8.1, 3J 4.9 Hz), 4.53 d (1Н, Н11A, J 11.1 Hz),
7.09–7.11 m (3Н, Н7–9), 7.19 d (2Н, Н2',6', J 8.6 Hz),
7.54 d (1Н, Н6, J 6.7 Hz), 7.61 d (2Н, Н3',5', J 8.6 Hz).
Found, %: N 14.37. С17Н14FN3О. Calculated, %: N
14.23.
3
2
3
3
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6.0 Hz), 2.42 s (3Н, Me), 3.57 t (2Н, NСН2, J 7.5 Hz),
4.20 t (2Н, ОСН2, J 6.0 Hz), 5.82 br.s (1Н, ОН),
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1
204–205°С (EtOН) (199–200°C [9]). Н NMR spec-
trum (DMSO-d6), δ, ppm: 1.88 t (2Н, СН2СН2СН2, J
6.6 Hz), 4.11 t (2Н, NСН2, J 7.2 Hz), 4.69 t (2Н,
ОСН2, J 5.1 Hz), 7.07 t (1Н, Н6 or 7, J 7.5 Hz), 7.21 t
(1Н, Н 7 or 6, J 7.5 Hz), 7.51–7.59 m (3Н, Н5 or 8,2',6'),
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